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Fairgrieve S.,Institute of Genetic Medicine
Nursing standard (Royal College of Nursing (Great Britain) : 1987) | Year: 2013

This is the eighth article in a series looking at how nurses can develop competence in genetics and genomics health care. The article explores the many ways in which nurses can acquire up to date and accurate genetic and genomic information, with the intention of improving their knowledge base. It enables nurses to discover the best ways of giving specific and complex information to patients and colleagues effectively and using straightforward language.

Blaum B.S.,University of Tubingen | Hannan J.P.,Aurora University | Herbert A.P.,University of Edinburgh | Kavanagh D.,Institute of Genetic Medicine | And 3 more authors.
Nature Chemical Biology | Year: 2015

The serum protein complement factor H (FH) ensures downregulation of the complement alternative pathway, a branch of innate immunity, upon interaction with specific glycans on host cell surfaces. Using ligand-based NMR, we screened a comprehensive set of sialylated glycans for binding to FH and solved the crystal structure of a ternary complex formed by the two C-terminal domains of FH, a sialylated trisaccharide and the complement C3b thioester-containing domain. Key residues in the sialic acid binding site are conserved from mice to men, and residues linked to atypical hemolytic uremic syndrome cluster within this binding site, suggesting a possible role for sialic acid as a host marker also in other mammals and a critical role in human renal complement homeostasis. Unexpectedly, the FH sialic acid binding site is structurally homologous to the binding sites of two evolutionarily unrelated proteins. The crystal structure also advances our understanding of bacterial immune evasion strategies. © 2015 Nature America, Inc. All rights reserved.

Martin E.A.,Cedars Sinai Medical Center | Barresi R.,Institute of Genetic Medicine | Byrne B.J.,University of Florida | Tsimerinov E.I.,Cedars Sinai Medical Center | And 7 more authors.
Science Translational Medicine | Year: 2012

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective - causing functional muscle ischemia - in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3′,5′-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.

Burn J.,Institute of Genetic Medicine | Mathers J.,Northumbria University | Bishop D.T.,University of Leeds
Recent Results in Cancer Research | Year: 2013

Hereditary forms of colorectal cancer account for less than 5 % of colorectal cancer but attract disproportionate attention because they offer an opportunity for effective surgical prophylaxis, influence the health of the wider family and give insight into the critical pathways of carcinogenesis. Familial Adenomatous Polyposis (FAP) due to loss of the APC gene and Lynch syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC) due to breakdown in MisMatch Repair are the principal syndromes of broader interest and both have been the subject of chemoprevention trials. There has been a longstanding interest in non-steroidal anti inflammatories in FAP where trials have shown regression of polyps with the pro drugsulindac and the selective COX2 inhibitors though impact on long-term cancer risk is not confirmed. The CAPP1 trial focused on two interventions in a factorial design, aspirin and resistant starch or fermentable fibre. Resistant starch is not absorbed in the small intestine and undergoes colonic fermentation to short-chain fatty acids including butyrate which have anti-cancer effects. Polyposis registry clinicians across Europe recruited adolescents with FAP to receive aspirin (600 mg as 2 tablets/d) and/or 30 g as 2 sachets/d in a 1:1 blend of potato starch and high amylose maize starch [Hylon VII]) with placebo control for at least a year or until surgery before age 21. Fifty-nine percent (133/227) of recruits had a baseline and at least one other endoscopy. After a median of 17 months, the primary endpoint of a risk of an increased polyp number in the rectum and sigmoid colon was not significantly reduced in either treatment group with relative risks of 0.77 (aspirin; 95 % CI, 0.54-1.10;) and 1.05 (RS; 95 % CI, 0.73-1.49. The diameter of the largest polyp detected tended to be smaller in the aspirin arm. The planned subgroup analyses of patients who elected to continue on study for more than one year found a significant reduction in the size of the largest polyp in the aspirin versus non-aspirin group (p = 0.02), Mean crypt length decreased significantly over time on study in the two combined RS groups, compared with the two combined non-RS groups (p < 0.0001 for interaction), in a model of the interaction between intervention and time. In CAPP2, 1009 Lynch syndrome gene carriers were recruited from 43 international centres. 937 commenced intervention: 600mg enteric coated aspirin and/or 30grams of the resistant starch Novelose in a 2 by 2 factorial placebo controlled design. After a mean of 29 months, intervention, there was no evidence that either agent influenced development of colonic neoplasia. However, the design included double blind follow-up for at least 10 years. After a mean of 55.7 months, and despite regular colonoscopy and polyp removal, 48 recruits developed CRC. Of these, 18 received aspirin and 30 received AP; the HR for CRC for aspirin was 0.63 (CI 0.35-1.13, p = 0.12). Five of the 48 people who developed CRC each had two primary colon cancers. Poisson regression analysis to allow for multiple primary events indicated a protective effect: IRR 0.56 (CI 0.32-0.99, p = 0.05). For those who took aspirin (or AP) for a minimum of 2 years (per protocol) the HR was 0.41 (CI 0.19-0.86 p = 0.02) and the IRR, 0.37 (CI 0.18-0.78 p = 0.008). Combined analysis of all LS cancers including CRC revealed a similar effect. On intention to treat analysis, the HR was 0.65 (CI 0.42-1.00, p = 0.05 and IRR was 0.59 (CI 0.39-0.90 p = 0.01), while the Per Protocol analysis HR was 0.45 (CI 0.26-0.79 p = 0.005,) and IRR was 0.42 (CI 0.25-0.72, p = 0.001). Adverse events in the aspirin and placebo groups were similar with 11 significant gastrointestinal bleeds or ulcers in the aspirin group and 9 in the placebo group. The evidence is now sufficient to recommend aspirin to all Lynch syndrome gene carriers. CAPP3 will recruit 3000 gene carriers into a dose inferiority study to test the relative benefits of 100mg, 300 or 600mg daily doses. © 2013 Springer-Verlag Berlin Heidelberg.

Razavi S.,Isfahan University of Medical Sciences | Razavi M.R.,Pasteur Institute of Iran | Kheirollahi-Kouhestani M.,Institute of Genetic Medicine | Mardani M.,Isfahan University of Medical Sciences | Mostafavi F.S.,Isfahan University of Medical Sciences
Biochemical and Biophysical Research Communications | Year: 2013

Adipose-derived stem cells (ADSCs) and bone marrow stem cells (BMSCs) can be equally proper in the treatment of neurodegenerative diseases. However, ADSCs have practical benefits. In this study, we attempted to induce the secretion of neurotrophic factors (NTF) in human ADSCs. We then evaluated the effects of co-culture with NTF secreting cells in neural differentiation of human ADSCs. Isolated human ADSCs were induced to neurotrophic factors secreting cells. To evaluate the in vitro effects of NTF-secreting ADSCs on neurogenic differentiation of ADSCs, we used neurogenic induction medium (control group), the combination of neurogenic medium and conditioned medium, or co-cultured NTF-secreting ADSCs which were encapsulated in alginate beads (co-culture) for 7. days. ELISA showed increased (by about 5 times) release of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in NTF-secreting ADSCs compared to human ADSCs. Real time RT-PCR analysis revealed that NTF-secreting ADSCs highly expressed NGF and BDNF. In addition, co-culture with NTF-secreting ADSCs could also promote neuronal differentiation relative to gliogenesis. Overall, NTF-secreting ADSCs secrete a range of growth factors whose levels in culture could promote neuronal differentiation and could support the survival and regeneration in a variety of neurodegenerative diseases. © 2013 Elsevier Inc.

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